Trypanosoma brucei

Background

• Causes African trypanosomiasis, also known as African sleeping sickness

	West African	East African
Organism	T. b. gambiense	T. b. rhodesiense
Vector	tsetse fly, palpalis group	tsetse fly, morsitans group
Habitat	forests and wooded areas	savanna and woodlands
Primary reservoir	humans	antelope and cattle
Human illness	chronic (late CNS disease)	acute (early CNS disease)
Duration of illness	months to years	< 9 months
Lymphadenopathy	prominent	minimal
Parasitemia	low	high
Epidemiology	rural	tourists and workers in game parks/wild areas; rural
Treatment	pentamidine (non-CNS) or eflornithin (CNS)	suramin (non-CNS) or melarsoprol (CNS)

Microbiology

• Vector-borne flagellated protozoan parasite transmitted by the tsetse fly belonging to the genus Trypanosoma, subgenus Trypanozoon
• Two subspecies that are morphologically indistinguishable
  • T. b. gambiense, causing chronic African trypanosomiasis (“West African sleeping sickness”)
  • T. b. rhodesiense, causing acute African trypanosomiasis (“East African sleeping sickness”)
  • Also, T. b. brucei, which infects cattle and occasionally other animals
• No intracellular phase, in contrast to Chagas disease

Epidemiology

• Present only in sub-Saharan Africa
• Transmitted by flies in the genus Glossina (tsetse flies) in their saliva during feeding
  • Tsetse flies exists only in Africa
• Animal reservoirs include cattle and possibly wild ungulates (T. b. rhodesiense); non-human animals are less important for T. b. gambiense

Pathophysiology

• Procyclic trypomastigotes develop in the midgut then migrate to the salivary glands, where they develop into epimastigotes and then metacyclic trypomastigotes
• Metacyclic trypomastigotes are transmitted in the saliva during feeding
  • Local replication in the trypanosomal chancre followed by lymphatic and hematogenous dissemination
• They multiply in the bloodstream and are thus exposed continuously to the immune system
  • They undergo antigenic variation to periodically change their external glycoprotein structures (VATs)
  • VAT: variant antigen type

Clinical Manifestations

• Almost all cases lead to death if not treated

West African trypanosomiasis

• Typically more chronic than East African trypanosomiasis

Trypanosomal chancre

• Incubation period of 1 to 2 weeks
• Painful, indurated trypanosomal chancre, which resolves after several weeks
  • May ulcerate
  • May have regional lymphadenopathy
  • Often not present

Stage 1 disease (hemolymphatic)

• Incubation period weeks to months
• Intermittent high fever lasting days, with intervening afebrile periods
• Lymphadenopathy develops
  • Winterbottom sign: enlargement of posterior cervical lymphadenopathy
• Hepatosplenomegaly
• Transient edema in face, hands, feed, and periarticular areas
• Pruritis, often with an irregular erythematous circinate rash on trunk, shoulders, buttocks, and thighs (5-10 cm with central clearing)
• May also have malaise, headache, weakness, weight loss/cachexia, arthralgias, and tachycardia
• Anemia, thrombocytopenia
• Mott cells on tissue biopsy

Stage 2 disease (meningoencephalitic)

• Multiple neurological manifestations are possible, following months to years of infection
  • Irritability, personality changes, and loss of concentration may be the earliest symptoms
  • Progressive indifference with daytime somnolence and sometimes restlessness and insomnia at night
  • Headache is common
  • Extrapyramidal signs with choreiform movements, tremors, fasciculations
  • Ataxia
  • Parkinsonian features
  • Coma and death over weeks to months
• CSF should be abnormal, with elevated protein and WBCs
• Extraneurological symptoms may include hypothyroidism and adrenal insufficiency (not necessarily confirmed on bloodwork)

East African trypanosomiasis

• Typically more acute than West African trypanosomiasis
• Incubation period of days to weeks
• In returned travelers, may present with fever, malaise, and headache
• Fever becomes intermittent and a rash develops
• Lymphadenopathy is less prominent
• Persistent tachycardia
• No clear distinction between hemolymphatic and meningoencephalitic stages
• Patients may die from arrhythmias or heart failure related to pancarditis
• Untreated, death within weeks to months

Diagnosis

• Diagnosis requires demonstration of parasite in tissue or fluid on microscopy, including CSF in all patients
  • For chancre, express fluid and examine under light microscopy for motile trypanosomes
  • Fix and stain with Giemsa
  • Aspiration of lymph nodes with kneading (may need multiple aspirates)
  • Thin and thick Giemsa stained blood films is most useful in hemolymphatic stage
• PCR and LAMP may be sensitive and specific but is not currently well-enough developed

Management

• Treatment is more toxic in meningoencephalitic stage
• Monitor for side effects during treatment (common)

CDC Guidelines

Species	Drug	Adult Dosage	Pediatric Dosage
T. b. rhodesiense, hemolymphatic stage	Suramin	1 gm IV on days 1, 3, 7 ,14, and 21	20 mg/kg IV on days 1, 3, 7, 14, and 21
T. b. rhodesiense, CNS involvement	Melarsoprol	2-3.6 mg/kg/day IV x 3 days. After 7 days, 3.6 mg/kg/day x 3 days. Give a 3rd series of 3.6 mg/kg/d after 7 days.	2-3.6 mg/kg/day IV x 3 days. After 7 days, 3.6 mg/kg/day x 3 days. Give a 3rd series of 3.6 mg/kg/d after 7 days.
T. b. gambiense, Hemolymphatic stage	Pentamidine	4 mg/kg/day IM or IV x 7-10 days	4 mg/kg/day IM or IV x 7-10 days
T. b. gambiense, CNS involvement	Eflornithine	400 mg/kg/day in 4 doses x 14 days	400 mg/kg/day in 4 doses x 14 days

• Patients should be followed with a lumbar puncture every 6 months (or sooner, if symptoms return) for 2 years after treatment to detect a relapse should it occur
• New treatment, fexinidazole, may be a reasonable oral treatment

Prevention

• Vector control programs
• Treatment of infected humans and animals
• Vector avoidance with insect repellant, long-sleeve clothes, and avoiding known endemic areas